Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis

BACKGROUND: Hemophilia A is often viewed as a male disease; females are usually considered asymptomatic hemophilia A carriers. However, hemophilia A carriers may experience mild-to-severe bleeding events. OBJECTIVE: To compare clinical characteristics, health care resource utilization, and costs incurred by hemophilia A carriers compared with a non–hemophilia A carrier female control population in the United States. METHODS: This retrospective observational cohort study used data from IBM MarketScan Commercial Claims and Encounters and Multi-State Medicaid Databases from January 1, 2016, to September 30, 2019. Patients with a hemophilia A carrier diagnosis were matched to a non–hemophilia A carrier female control group in a 1:2 ratio based on sociodemographic characteristics, pregnancy status, and insurance type. Billed annualized bleed rates, health care resource utilization, and annualized costs were evaluated. Generalized linear models compared annualized total costs in the hemophilia A carrier and control groups. RESULTS: After matching, the hemophilia A carrier group included 121 (Commercial) and 55 (Medicaid) patients, matched 1:2 in the control group. Patients in the hemophilia A carrier group (compared with the control group) had numerically higher joint-related health issues (Commercial: 11.6% vs 7.9%; Medicaid: 7.3% vs 4.5%) and lower soft-tissue disorders (Commercial: 13.2% vs 17.4%; Medicaid: 12.7% vs 14.5%). Musculoskeletal pain was higher (33.1% vs 31.0%) and lower (21.8% vs 25.5%) in the Commercial and Medicaid databases, respectively. Billed annualized bleed rates were higher in the hemophilia A carrier group (Commercial: 0.49 vs 0.33; Medicaid: 0.50 vs 0.29). Significantly more patients in the hemophilia A carrier group had minor bleeds (Commercial: 34.7% vs 22.3% [P = 0.001]; Medicaid: 43.6% vs 20.0% [P < 0.001]) and spontaneous bleeds (Commercial: 35.5% vs 21.5%; Medicaid: 47.3% vs 23.6% [P < 0.001 for both]). Outpatient visits represented the majority of health care resource utilization and were higher in the hemophilia A carrier group for all-cause and bleed-related claims; although less frequent, emergency department and inpatient visits followed a similar trend. In the Commercial and Medicaid databases, hemophilia A carriers incurred approximately 2 times higher mean (SD) all-cause health care total costs than patients in the control group (Commercial: $15,345 [21,871] vs $8,358 [11,939] per patient per year [PPPY]; Medicaid: $9,022 [19,461] vs $4,533 [9,532] PPPY). CONCLUSIONS: Hemophilia A carriers experienced more complications and incurred higher costs (resulting from more outpatient, emergency department, and inpatient visits) compared with patients in the control group. These data suggest that hemophilia A carriers have a high disease and economic burden and may benefit from early diagnosis and management to prevent long-term complications.


RESULTS:
After matching, the hemophilia A carrier group included 121 (Commercial) and 55 (Medicaid) patients, matched 1:2 in the control group. Patients in the hemophilia A carrier group (compared with the control group) had numerically higher joint-related health issues (Commercial: 11.6% vs 7.9%; Medicaid: 7.3% vs 4.5%) and lower soft-tissue disorders (Commercial: 13

Plain language summary
Hemophilia A carriers are females with a modified gene that causes hemophilia A, a bleeding disorder. Carriers are often perceived to have no bleeding symptoms. This study shows that carriers may have greater bleeding risk, number of doctor visits, and health-related costs than females without the affected gene. Health issues of carriers are often discovered later in life such as during pregnancy. An earlier diagnosis may help decrease carriers' health issues and associated costs.

Implications for managed care pharmacy
Hemophilia A carriers, often diagnosed later in life (eg, during pregnancy), had more complications and higher health care resource utilization and costs than a control population of noncarrier females in the United States. These results confirm that hemophilia A carriers may be symptomatic. Hemophilia A carriers with low factor VIII and/or bleeding symptoms should be identified early to ensure adequate care. Early management of hemophilia A carriers may reduce long-term health care resource utilization and costs.
Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis needs, in 2021, the Medical and Scientific Advisory Council of the National Hemophilia Foundation put forward recommendations for the management of bleeding disorders in girls and women. They emphasized the need for continued efforts to raise awareness to ensure girls and women with a bleeding disorder receive a correct and timely diagnosis, as well as proper access to care. 18 Bleeding risk and presentation, complications, and treatment guidelines for hemophilia A carriers in the United States are not well defined. 3 Moreover, limited real-world evidence exists for the diagnosis and management of females with a diagnosis of hemophilia A or hemophilia A carrier, despite their tendency to experience bleeding symptoms. Since 2015, the International Classification of Diseases, Tenth Revision (ICD-10) nomenclature differentiates diagnoses of hemophilia A, symptomatic hemophilia A carriers, and asymptomatic hemophilia A carriers. In 2021, the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis introduced a new nomenclature based on FVIII levels and defined hemophilia A carriers with FVIII levels less than 40 IU/dL as females with hemophilia A rather than as symptomatic carriers. 19 There is now an opportunity to study potential effects on hemophilia A carrier care outcomes using data from insurance databases. Large samples derived from administrative health insurance claims are valuable in studying rare conditions such as hemophilia 20 and contain patient characteristics, cost, and health care utilization data that can provide real-world information on the burden of illness.
This study aimed to compare sociodemographic and clinical characteristics, health care resource utilization (HCRU), and costs incurred by hemophilia A carriers with a matched non-hemophilia A carrier general female control population in the United States. This analysis provides real-world evidence of the current management of care received by hemophilia A carriers in the United States and highlights any unmet needs that remain to be addressed including delays in diagnosis, as well as the recognition of carriers' symptoms and need for treatment.

STUDY DESIGN
This retrospective observational cohort study used administrative claims from the IBM MarketScan Research Databases, including the Commercial Claims and Encounters (Commercial) and Multi-State Medicaid (Medicaid) databases from January 2016 through September 2019 (Supplementary Figure 1, available in online article). 21 Deidentified and anonymized claims data were collected retrospectively in compliance with the Health Insurance 47.3% vs 23.6% [P < 0.001 for both]). Outpatient visits represented the majority of health care resource utilization and were higher in the hemophilia A carrier group for all-cause and bleed-related claims; although less frequent, emergency department and inpatient visits followed a similar trend. In the Commercial and Medicaid databases, hemophilia A carriers incurred approximately 2 times higher mean (SD) all-cause health care total costs than patients in the control group (Commercial: $15,345 [21,871]  CONCLUSIONS: Hemophilia A carriers experienced more complications and incurred higher costs (resulting from more outpatient, emergency department, and inpatient visits) compared with patients in the control group. These data suggest that hemophilia A carriers have a high disease and economic burden and may benefit from early diagnosis and management to prevent long-term complications.
Hemophilia A is an X-linked genetic disease resulting from mutation of the factor VIII (FVIII) gene. 1 The estimated prevalence of hemophilia A in the United States is 12 per 100,000 males; however, the prevalence of females with a diagnosis of hemophilia A or hemophilia A carrier is not well studied. [1][2][3][4][5] In hemophilia A carriers, FVIII levels vary substantially and can be less than 50 IU/dL (< 50% of the values found in healthy individuals 6 ), which may not be adequate for normal hemostasis. [6][7][8] Mildly reduced clotting factor levels (between 41 and 60 IU/dL) have been shown to be associated with bleeding, although bleeding symptoms can also occur among hemophilia A carriers with higher FVIII levels, suggesting that the bleeding phenotype only partially correlates with factor levels. [9][10][11][12] In a descriptive analysis of bleeding symptoms in hemophilia A carriers enrolled in the American Thrombosis and Hematology Network dataset, 13,14 23.5% of hemophilia A carriers with an FVIII level greater than or equal to 40 IU/dL reported an abnormal bleeding score. 15 A recent systematic review showed that hemophilia A carriers have a higher prevalence of hemorrhagic symptoms (eg, excessive wound bleeding, heavy menstrual bleeding, postpartum bleeding, mucosal bleeding, hemarthroses, and bleeding after surgical procedures) than non-hemophilia A carriers. 12 Owing to a lack of awareness, hemophilia A carriers' most prevalent symptom of heavy menstrual bleeding is often overlooked by general practitioners and gynecologists; thus, hemophilia A carriers are rarely referred to a hematologist and face unique challenges during their reproductive years. 9,16,17 Hemophilia A carriers experience a higher rate of pregnancy-related bleeding complications, especially during the postpartum period. 9,16,17 In addition, hemophilia A carriers have been shown to have an increased risk of joint-related health issues compared with non-hemophilia A carriers. 10, 11 In response to these unmet Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis disorders, were collected (ICD-10-CM diagnosis codes used for collection did not overlap for each of the 3 categories) (Supplementary Table 1). Pregnancy and delivery were documented during the baseline and follow-up periods. The use of other supportive medications (antianemia medications, pain medications, aminocaproic acid, tranexamic acid, and hormonal contraceptives) was explored.

BLEEDING EVENTS
Billed bleeding events that resulted in an interaction with the health care system (inpatient, ED, or outpatient visits) were captured using diagnosis information from medical claims during the baseline and follow-up periods. Bleeding events were grouped as major (patients with ≥ 1 inpatient or ED bleeding ICD-10 codes in the primary or secondary diagnosis position) and minor (patients with ≥ 1 outpatient bleeding ICD-10 codes in any diagnosis position). Spontaneous or traumatic bleeds were captured as ≥ 1 inpatient or ED bleeding ICD-10 codes in the primary or secondary diagnosis position or ≥ 1 outpatient bleeding ICD-10 codes in any diagnosis position during the baseline and follow-up periods combined. All bleeds caused by a contusion or another injury were classified as traumatic bleeds. Bleeds that occurred in the absence of overt trauma were classified as spontaneous bleeds. Thus, spontaneous bleeds included excessive menstrual bleeding, peri/postpartum complication, circulatory hemorrhage, respiratory bleeding, eye bleeds, ear bleeds, mouth/gum bleeds, hematuria, digestive bleeds, and musculoskeletal and soft-tissue bleeds and were calculated as the total reported bleeding events (defined as a cluster of bleeding claims for the same body part within a 7-day period 23 ) in the reporting window divided by the number of months and multiplied by 12; bleeding claims for different body parts were considered separate events if the bleeds began on separate days.

HEALTH CARE RESOURCE UTILIZATION
All-cause, bleed-related, and joint-related HCRU and costs were evaluated and reported as per patient per year (PPPY) for the hemophilia A carrier and control groups. HCRU and costs for the Commercial and Medicaid data were categorized into "all-cause" and "bleeding-related" inpatient visits, calculated as mean PPPY costs and inflation-adjusted to 2020 US dollars. The average length of stay per hospitalization was calculated as the total length of stay for all inpatient visits divided by the total number of inpatient visits.

STATISTICAL ANALYSIS
Descriptive statistics, including means, SDs, and medians for continuous variables and frequencies and percentages for categorical variables, were reported for sociodemographic and clinical characteristics, HCRU, and costs among Portability and Accountability Act; informed consent forms were therefore not collected. Claims data included medical and surgical codes, inpatient services, inpatient admissions, outpatient services, prescription drugs, long-term care, and other medical care. Inpatient visits correspond to hospitalizations; outpatient visits were divided into emergency department (ED) and non-ED visits.
The study included commercially insured and Medicaid hemophilia A carriers aged 0 to 89 years with 1 or more inpatient or outpatient diagnoses (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes Z14.01 and Z14.02) during the index period (July 2016 through September 2018). Patients with 2 or more claims at least 30 days apart for hemophilia B or other bleeding disorders, interrupted plan enrollment (defined by a gap in medical and pharmacy benefits of ≥ 45 days), or claims for male hemophilia A carriers without any claims for hemophilia A were excluded. Patients with FVIII inhibitors (identified from coagulation factor VIIa/anti-inhibitor coagulant complex claims) or those with claims for immune tolerance induction therapy (identified as described previously 22 ) were also excluded.

SELECTION OF THE MATCHED CONTROL POPULATION
The control population was obtained from a random sample of 10,000 female enrollees without a diagnosis of hemophilia A/hemophilia A carrier or other bleeding disorders. Thus, patients with claims for hemophilia A/hemophilia A carrier diagnosis, hemophilia medications, hemophilia B, other coagulation defects, and other hemorrhagic conditions during the study period were excluded.
Hemophilia A carriers were matched 1:2 to controls using the following criteria: sex, pregnancy status, insurance type (Commercial and Medicaid), region (Commercial only, because Medicaid does not provide these data), dual eligibility for Medicare (Medicaid only), index date (± 90 days; the index date was defined as the date of first diagnoses for hemophilia A, hemophilia A carrier, or treatment initiation during the index period), and age (± 1 year).

SOCIODEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Sociodemographic characteristics were described and included age, index year, region, insurance plan type, and dual eligibility for Medicaid and Medicare. Charlson Comorbidity Index scores were calculated based on the presence of diagnosis codes on medical claims obtained for baseline (6 months preceding the index date) and followup (12 months following the index date) periods combined. Hemophilia A-relevant symptoms, including joint-related health issues, musculoskeletal pain, and soft-tissue the hemophilia A carrier and control groups. Bivariate analysis was performed between the hemophilia A carrier and control groups to compare the patient sociodemographic and clinical characteristics: t-tests/paired t-tests and chi-square/McNemar tests for continuous variables and categorical variables, respectively. All-cause, bleed-related, and joint-related total cost outcomes were compared between the hemophilia A carrier and control groups using generalized linear models adjusted for sociodemographic and clinical characteristics. Separate regressions were framed for each outcome. The list of covariates was selected after examining the variables for which a significant difference existed between the hemophilia A carrier and control groups. However, variables with a causal link between hemophilia A carrier status and health care costs were not included as a covariate in the model.

SOCIODEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Prematching demographic characteristics for patients in the hemophilia A carrier (n = 138 and n = 67, in the Commercial and Medicaid databases, respectively) and control (n = 2,814 and

HEMOPHILIA A-RELEVANT SYMPTOMS
In both databases, joint-related health issues tended to be higher in the hemophilia A carrier than in the control groups (Commercial: 11.6% vs 7.9%; Medicaid: 7.3% vs 4.5%). Musculoskeletal pain was reported in 33.1% (Commercial) and 21.8% (Medicaid) of patients in the hemophilia A carrier group and 31.0% (Commercial) and 25.5% (Medicaid) of patients in the control group. Soft-tissue disorders were generally lower in the hemophilia A carriers than in the control groups for both Commercial (13.2% vs 17.4%) and Medicaid (12.7% vs 14.5%) patients ( Figure 1).

BLEEDING CHARACTERISTICS
Mean billed annualized bleed rates were numerically higher in the hemophilia A carrier group compared with the control group in the Commercial and Medicaid databases ( Figure 2).

Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis
A significantly higher number of minor bleeds was observed in the hemophilia A carrier group (Commercial: P = 0.001; Medicaid: P < 0.001); major bleeds presented a similar trend, but it was not statistically significant. Spontaneous bleeds were significantly more frequent (P < 0.001 for both databases) in the hemophilia A carrier group, whereas traumatic bleeds were numerically higher (Medicaid only) (Supplementary Figure 2). Heavy menstrual bleeding was more frequent in the hemophilia A carrier group in both databases (Commercial: 19.8% vs 11.6%; Medicaid: 23.6% vs 14.5%) and represented the most reported type of spontaneous bleed.

OTHER SUPPORTIVE MEDICATION USE
In the Commercial database, among hematology-related medications (antianemia medications, aminocaproic acid, and tranexamic acid), claims for antianemia intravenous medication and tranexamic acid were significantly higher in the hemophilia A carrier group compared with the control group (P = 0.020 and P = 0.007, respectively); however, the use of these medications was very low overall. No significant differences were observed for hematology-related medications for the patients in the Medicaid database (Supplementary Table 3). Within each database, opioid and nonopioid pain medication use was similar in the hemophilia A carrier and control groups (Supplementary Table 3).
Among hormonal contraceptives, estrogen/progestin products were most commonly used and were similar in the hemophilia A carrier and control groups for both databases. In the Medicaid database, medroxyprogesterone use was significantly higher (P = 0.035) among patients in the control group compared with the hemophilia A carrier group; however, only a few patients received medroxyprogesterone in each group. The use of hormone-releasing intrauterine devices, some of which are indicated to prevent heavy menstrual bleeding, was similar in the hemophilia A carrier and control groups (Supplementary Table 3).    In each database, outpatient visits represented the most all-cause, bleed-related, and joint-related claims. Patients in the hemophilia A carrier group had higher all-cause and bleed-related outpatient visits compared with the control group in both databases. Joint-related outpatient claims were higher in the hemophilia A carrier group in the Commercial database and lower in the Medicaid database ( Figure 3). Patients in the hemophilia A carrier group had higher or similar all-cause and bleed-related inpatient or ED visits in both databases. Joint-related inpatient and ED visits were similar between the hemophilia A carrier and control groups in both databases (Supplementary Figure 3).

TABLE 2
Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis higher use of tranexamic acid and antianemia intravenous medications suggest that patients in the hemophilia A carrier vs control groups may be treated on-demand for persistent heavy bleeding. Furthermore, despite heavy menstrual bleeding being considered the most commonly reported type of bleeding in hemophilia A carriers, both groups surprisingly had similar use of hormonal contraceptives, which could have been used to partially help decrease heavy menstrual bleeding. 17 Together, these results suggest that the patients in the hemophilia A carrier group might not receive adequate care. Overall, patients in the hemophilia A carrier group had higher all-cause and bleed-related inpatient, ED, and outpatient visits than patients in the control group. In addition, all-cause costs were higher for patients in the hemophilia A carrier group. These data reflect the higher health and economic burden incurred by hemophilia A carriers compared with females without a hemorrhagic condition.
Other studies reported that hemophilia A carriers have factor levels less than 60% of normal (approximately onethird of hemophilia A carriers); however, hemophilia A carriers with greater than 60% of normal clotting factor levels were also susceptible to bleeding events. 10,27,28 In the absence of family history, hemophilia A carriers can go undiagnosed for years until they experience heavy menstrual bleeding or bleeding after childbirth-symptoms that also occur in females without hemophilia. 26,27 This confirms the need for earlier diagnosis of hemophilia A carriers and provides an opportunity to redefine traditional factor level thresholds (based on the phenotype observed in males with hemophilia A), as factor levels in hemophilia A carriers are not always correlated with bleeding phenotype. 10, 19 Despite recent evidence suggesting an increased disease burden or worsened health-related quality of life, hemophilia A carriers continue to be underdiagnosed and undertreated. 27,29 This is further highlighted by the current study showing increased bleeding tendency, HCRU, and costs in patients in the hemophilia A carrier group compared with the control group. Additional studies focusing on primary data collection from hemophilia A carriers would add to this study by providing an understanding of the frequency and impact of at-home and outpatient bleeds. Furthermore, future research compiling data from multiple datasets would enhance the findings of this study.

LIMITATIONS
The results are only applicable to Commercial-and Medicaidinsured patients who meet eligibility criteria of our study; thus, they are not generalizable to the overall hemophilia A carrier population in the United States. 30 Furthermore, administrative claims data may not reflect accurate clinical patterns, 30 as information on diagnosis, treatment, and carrier) and 81.5% (control) of total costs; pharmacy costs were 18.8% (hemophilia A carrier) and 18.5% (control) of total costs (Table 2).

COMPARISON OF HEALTH CARE COSTS BETWEEN HEMOPHILIA A CARRIERS AND CONTROLS USING GENERALIZED LINEAR MODELS
In the Commercial database, all-cause, bleed-related, and joint-related costs were reported in 100%, 28%, and 34% of patients, respectively; 82%, 24%, and 16% patients reported costs in the Medicaid database. In this analysis, patients in the hemophilia A carrier group still had significantly higher all-cause total costs compared with patients in the control group after adjustment to covariates (Commercial: P = 0.001; Medicaid: P = 0.005). A similar trend was observed for bleed-and joint-related costs in hemophilia A carriers vs patients in the control group (Supplementary Table 4).

Discussion
This study compared clinical characteristics, medication use, HCRU, and costs between hemophilia A carriers and a matched control female population without hemorrhagic conditions in Commercial-and Medicaid-insured populations using administrative claims data to understand the burden of illness of hemophilia A carriers vs non-hemophilia A carrier females with similar sociodemographic characteristics and pregnancy status. The results revealed that pregnancy was reported in approximately one-third of hemophilia A carriers in the Commercial database and in more than 50% in the Medicaid database, suggesting that hemophilia A carriers may experience a delay in diagnosis, and issues may be identified during pregnancy because of increased health care interactions.
Hemophilia A carriers also had numerically higher occurrences of joint-related health issues, a common symptom and major contributor to the disease burden of patients with hemophilia A, 24 and higher mean billed annualized bleed rates than patients in the control group. Joint bleeds ultimately result in arthropathy, which is associated with pain and decreased quality of life and may impact patients' ability to maintain school attendance and employment. 25 Early recognition and diagnosis of hemophilia A carriers by health care providers could help prevent future jointrelated complications. 26 Patients in the hemophilia A carrier group had a significantly higher number of minor and spontaneous bleeds than those in the control group. Major and traumatic bleeds trended higher in the hemophilia A carrier vs control groups (Supplementary Figure 2). In the Commercial database, the procedure codes may be erroneous or incomplete, patients may not have filled and used their prescriptions, and, in the case of this study, billed annualized bleed rates only account for bleeds that have resulted in an interaction with the health care system. Another limitation is that there is currently no validated claims algorithm to identify hemophilia A carriers and the positive predictive value is unknown. Some patients may have been tested but did not have a confirmed diagnosis of hemophilia A carrier. Additionally, some hemophilia A carriers may not have been tested or diagnosed and therefore were not identified in this study. Finally, this study did not analyze racial subgroups; thus, any discrepancies of care were not reported. Nonetheless, the very large sample size in the IBM MarketScan databases allowed for research including 176 patients (Commercial and Medicaid) on this unique patient population with a rare disease. In addition, this study provides a better understanding of the clinical and economic burden of illness for hemophilia A carriers compared with a general female population without bleeding disorders.

Conclusions
Patients in the hemophilia A carrier group incurred nearly twice the overall health care costs of patients in the control group after matching, resulting from more inpatient, ED, and outpatient visits than the general female population. These results reflect the higher disease and economic burden for hemophilia A carriers, which may be partly due to diagnosis later in life. Thus, hemophilia A carriers may benefit from early screening and referral to hemophilia treatment centers for closer management; this strategy would help provide adequate care, prevent long-term complications, and improve quality of life.

ACKNOWLEDGMENTS
Medical writing assistance was provided by Peggy Robinet, PhD, of Parexel, with funding from Takeda Pharmaceuticals U.S.A., Inc.

DISCLOSURES
Dr Xing, Dr Bullano, Dr Caicedo, and Mr Farahbakhshian are employees of Takeda Pharmaceuticals U.S.A., Inc., hold Takeda stocks, and have been granted restricted stock shares; Drs Xing and Caicedo received support from Takeda Pharmaceuticals U.S.A., Inc., for travel to THSNA 2022, where the data included in this manuscript were presented. Dr Batt received consulting fees from Complete HEOR Solutions (CHEORS) LLC for the protocol development, data analysis, and interpretation of this study; she also holds stocks from Merck and Sanofi. Ms Kuharic is an employee of the University of Illinois at Chicago and has been supported by a Takeda fellowship during the execution of the study. Ms Chakladar and Ms Markan were employees of CHEORS LLC at the time of the study. CHEORS has received funding from Takeda Pharmaceuticals U.S.A., Inc., for conducting the analysis of this study. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. The sponsor was involved in the study design; collection, analysis, and interpretation of data; development and review of the manuscript; and decision to submit manuscript to publication.